Leucocyte arrest on endothelial cells is mediated by selectin binding to endothelial lectins, resulting in slow rolling, followed by integrin-mediated arrest.45 Chemokine expression on the surface of endothelial cells triggers changes in leucocyte integrin affinity, resulting in rapid binding of β2-containing integrins to endothelial intercellular adhesion molecule-1 and α4-containing integrins to vascular cell adhesion molecule-1. Following arrest, there is rapid release of these integrin contacts allowing

leucocytes to move to endothelial cell junctions, and migrate through these junctions. Finally, phagocytes migrate through the tissue to bacterially infected areas. OPN or its fragments bind to the α4β1 and α9β1 integrins through the SLAYGLR sequence: these integrins

Sorafenib mw are important in all these steps of infiltration;46,47 hence OPN may be important in any of these aspects of phagocyte extravasation. The exact mechanism remains obscure, however, and further work is required to elucidate the molecular interactions. Important questions include whether OPN regulates the function of these cell types, or if its effect is mostly related to cell migration. The role of leucocyte extravasation in the development of mouse periapical lesions selleck chemicals was explored using P/E selectin double-deficient mice.48 These animals developed extensive bone loss similar to the OPN-deficient mice. There were also extensive systemic effects, including splenomegaly, which was not observed in the OPN-deficient mice (data not shown) and a 50% decrease in neutrophil accumulation in the inflammatory site. Hence, the effect of OPN deficiency on neutrophil accumulation is not as severe as that of selectin deficiency,

perhaps reflecting the redundancy of the integrin ligands available for extravasation. These integrins undergo rapid changes in affinity for their ligands during inflammation, and it is not known how these changes affect the binding of OPN.45,49,50 CD44 isoforms are also implicated in the effects of OPN,51 and additionally there is evidence that an intracellular form of OPN may have physiological importance.36,52 At early times after infection, we observed RVX-208 increased expression of IL-1α and RANKL in infected tissues from OPN-deficient mice: both these cytokines are associated with inflammation-associated bone resorption.26,53 Hence, the mechanism of the increased bone resorption in these mice is probably related to the increased expression of IL-1α and RANKL: further work is needed to determine the cell types expressing these factors in endodontic infections and the role of OPN in their regulation. OPN has been shown to be required for bone resorption in mice in response to ovariectomy or hind-limb suspension,54,55 and this effect is probably the result of a defect in osteoclast function in the absence of OPN.